RNA build-up linked to dementia and motor neuron disease

30 October 2013

A new
toxic entity associated with genetically inherited forms of dementia and motor
neuron disease has been identified by scientists at the UCL Institute of
Neurology.

The toxin is the result of a genetic mutation that leads to the
production of RNA molecules which could be responsible for the diseases. The
findings are published in the journal Acta
Neuropathologica.

The
most common known cause for both frontotemporal dementia and motor neuron
disease is an unusual genetic mutation in the C9orf72 gene. The mutation
involves a small string of DNA letters at the beginning of the gene, which
expand massively to produce thousands of copies.

The
new research, funded by Alzheimer’s Research UK and the Medical Research Council,
has shown that this DNA expansion acts in a peculiar way, leading to the
generation of unexpected RNA molecules that could cause the disease.

When a
gene is turned on, an RNA copy of the gene’s DNA is generated. The gene’s DNA
code has directionality, so that it is normally turned on in only one
direction, termed the ‘sense direction’. The new research shows that the DNA
expansion is turned on in both directions.

This
leads to the normal sense RNA being produced, as well as RNA in the opposite
direction, termed ‘antisense RNA’. Both RNA types accumulate into aggregates in
the neurons of people with frontotemporal dementia.

Intriguingly,
the research showed that people with more of these aggregates in their brains
developed the disease earlier than people with less RNA aggregates. This
correlation suggests that the build-up may be important in causing
frontotemporal dementia and motor neuron disease, making the C9orf72 DNA
expansion a potential target for therapy.

Dr
Adrian Isaacs, lead researcher at the UCL Institute of Neurology, said: ““These
findings identify new, potentially toxic molecules in diseases caused by DNA
expansions. The next steps will be to determine how they might kill neurons and
how to stop them building up.”

Dr Simon Ridley, Head of Research at Alzheimer’s
Research UK, the UK’s leading dementia research charity, said: “The discovery
of the C9ORF72 gene was a major step forward for research into frontotemporal
dementia and motor neuron disease, and it’s positive to see researchers
beginning to untangle how this gene may cause these diseases in some people.

“Alzheimer’s Research UK is delighted to have
supported this promising study. By unravelling some of the biological
mechanisms at play, this research could take us further on the road to new
treatments that are so desperately needed by the thousands of people with these
devastating diseases. For these results to reach their full potential it’s
vital that we continue to invest in research.”